Aromatic quaternary ammonium salts with disinfectant activity



United States Patent 3,390,158 AROMATIC QUATERNARY AMMONIUM SALTS WITH DISINFECTANT ACTIVITY Vladimir Janata and Viktor Bydzovsky, Prague, Czechoslovakia, assignors to Spofa, Sdruzeni Podniku pro Zdrovotnickou Vyrobu, Prague, Czechoslovakia No Drawing. Filed Nov. 30, 1964, Ser. No. 414,833 Claims priority, application Czechoslovakia, Dec. 5, 1963,

11 Claims. (Cl. 260-404) ABSTRACT OF THE DISCLOSURE Quaternary ammonium salts with disinfectant activity, of the general Formula I:

RyCH-COORZ I Y 9 (Rap-M0114 X G) wherein R is a straight or branched aliphatic chain with -16 carbon atoms, R is a straight or branched alkyl with l-8 carbon atoms, cycloalkyl or aralkyl, R is alkyl with l-4 carbon atoms, and the substituents Y and Z, identical or different, stand for hydrogen, halogen, or methoxy, and X is halogen.

The compounds of the invention are useful as disinfectants and can be made in solid crystalline form.

An example of the compounds of the invention is acarbethoxypentadecyl benzyldimethylammonium chloride.

The invention relates to new quaternary ammonium salts with disinfectant activity and to the method of preparing same.

Said salts are represented by the general Formula I:

Ri-CH-COOR2 wherein R is a straight or branched aliphatic chain with 1016 carbon atoms, R is a straight or branched alkyl with l-8 carbon atoms, cycloalkyl or aralkyl, R is an alkyl with 1-4 carbon atoms, and the substituents Y and Z, identical or different, stand for an atom of hydrogen, halogen, or a methoxy group, and X is a halogen atom, preferably chlorine.

The quaternary salts of the above quoted general Formula I represent altogether definable crystalline substances showing disinfectant effect enhanced by their surface activity. They are readily soluble in water, lower alcohols and glycols, capable of forming solutions of 30 percent or even higher concentrations, stable at normal tempera ture.

Crystalline and chemically homogenous substances of this kind are advantageous above all in that they can secure constant effectiveness of disinfectants prepared with them, that they can be used mostly in the form of aqueous solutions of various concentrations, and in that they offer the possibility of determining the disinfectant effect by external conditions, permitting the study of the mechanism of their effect, etc. From an economical standpoint also the shipment of crystalline substances appears more advantageous and easier than the expensive, uncomfortable, and sometimes diflicult to handle aqueous solutions.

Compared with known disinfectants, e.g. with N-alkylbenzyl-dimethylammonium halides, cetyltrimethylam-mo- 3,390,158 Patented June 25, 1968 ice R1. CHI) 0 0 R2 a)2=N II wherein R R and R have the same definition as in Formula I, is brought into reaction with a compound of the general Formula III Z III wherein X, Y, and Z have the same definition as in Formula I.

In carrying out the method according to the invention it is preferable to use a molar ratio of 11:1 for the two components of the general Formulas II and III.

The reaction can be carried out either without any medium, or in the medium of polar organic solvents, such as acetone, ether, ethly acetate, or dimet'hyl formamide, at a temperature within the range of normal temperature of 1525 up to C., and at atmospheric pressure, or with pressures up to 5 atm.

Under the conditions usually practised in the preparation of quaternary ammonium salts, the reaction of the components proceeds very slowly, and isolation of the product from the reaction mixture, containing still a large part of unreacted starting substances, is very difficult.

The advantageous preparation of substances of the general Formula I, according to the invention, is rendered possible by adjustment of the reaction conditions by addition of a slight amount of suitable solvents, application of a suitable temperature and concentration of the reacting components. Except for the solvents listed in the examples (i.e. acetone, ether, and dirnethyl formamide), also other polar solvents can be used, such as higher ketones, alcohols, esters, acetonitrile, nitromethane, and the like. Of special advantage are such solvents, by which the reaction of the two components is accelerated, and in which at the same time the reaction product is insoluble. In some instances the reaction can be effected without the use of any organic solvent.

In pharmacological testing the substances of the general formula I proved to have a relatively low toxicity in peroral application (LD =l44-380 mg./kg.--rnice),

and to be non-irritating. In bacteriological testing with Staphylococcus pyogenes aureus and Salmonella typhi there was shown at least double activity compared with known preparations, e.g. dodecylbenzyldimethylammonium bromide (Zephirol), or a c'arbethoxypentadecyhtrimethylammonium bromide (Brit. Pat. No. 961,353).

EXAMPLES decylbenzyl-dimethylammonium chloride, is Washed with acetone. The united filtrates are concentrated by evaporating the acetone, whereby a further portion of the crystalline quaternary salt is obtained. The total yield of the final product, Which on twofold recrystallization from acetone has M.P. 106 C., amounts to g.

(2) By reacting the butylester of ot-dimethylaminopal-mi'tic acid with benzyl chloride under the same conditions as in Example 1, there is obtained by stirring up the reaction mixture with ether, in which the quaternary salt formed is insoluble, filtration, Washing with ether and drying, the ot-carbobutoxypentadecyl-benzyldimethylammonium chloride in the form of a white crystalline substance with M.P. 74 C.

(3) By reacting g. ethylester of tt-dimethylaminopalmi'tic acid with 10 g. p-chlorobenzyl chloride under the same conditions as in Example 1, and using ether for isolation of the product, likewise as in Example 2, there is obtained a carbethoxypentadecyl p chlorobenzyldimethylam monium chloride in the form of a white crystalline substance with M.P. 126 C.

(4) 52.5 g. ethylester of wdimethylaminopalmitic acid is dissolved in ml. acetone, and to the solution the product is added that had been obtained in the known way by chloromethylation of 54 g. 'anisole by means of paraformaldehyde and gaseous hydrogen chloride, and containing in the mixture p-methoxybenzyl chloride with unreacted anisole. The reaction mixture is left to stand for 3 days at room temperature. The product crystallized is filtered off by suction, washed with acetone and dried. There is obtained 13 g. of a-carbethoxypentadecyl-ptmethoxybenzyl-dimethylammonium chloride in the form of a white crystalline substance with M.P. 112 C.

(5) 15 g. butylester of a-dimethylaminolauric acid is dissolved in 15 ml. acetone, 6.3 g. benzyl chloride is added With stirring, and the reaction mixture is then left to stand at rest for several days at room temperature. If there does not come to elimination of a crystalline product, crystallization is initiated by any of the known methods, e.g. inoculation. In that case the liquid reaction mixture does quickly crystallize throughout the mass under spontaneous warming up. After standing for 24 hours at room temperature the reaction product is filtered by suction, several times thoroughly washed with ether, and dried. There is obtained 9.2 g. a-carbobutoxyundecylbenzyl-dimet-hylammonium chloride in the form of a White crystalline substance with M.P. 87 C. On recrystallization from acetone the M.P. is 92 C.

(6) The quaternary salt described in Example 5 can be prepared also by heating 12 g. butylester of a-dimethylaminopalmitic acid with 5 g. benzyl chloride to 90 C. for 6 hours. After cooling down the reaction mixture is allowed to stand for 12 hours at room temperature, in order to get crystallized the major part of the quaternary salt formed, thereupon it is stirred up with ether, and further processed to the final product in the way already described.

(7) 8 g. cyclohexylester of u-dimethylaminolauric acid is stirred up with 3.2 g. benzyl chloride to a homogeneous solution, which is then kept :at a temperature of 40 C. for 7 days. The crystallized quaternary salt is filtered by suction and washed with ether. The united filtrates are freed of the ether by evaporation, and the liquid residue is heated to 60 C. for 3 days. There crystallizes a further portion of the quaternary salt, which is then sucked off and washed with ether. There is obtained altogether 6.3 g. of crude quaternary salt having M.P. 118 C. By repeated crystallization the pure cz-Cl-IbOCYClOhCXYlOXY- undecyl-benzyldimethylammonium chloride is prepared, in the form of a white crystalline substance with M.P. 133 C.

The mother liquor obtained in the crystallization of the crude quaternary salt is evaporated and the residue extracted with 15 ml. water and 7.5 ml. ether. The aqueous extract is washed with ether, the ethereal extract in turn with water, and both evaporated. From the aqueous extracts further 1.5 g. of the crude quaternary salt is obtained, and from the ethereal extracts 2 g. of the unreacted starting cyclohexylester of tit-dimet-hylaminolauric acid recovered.

(8) The quaternary salt described in Example 7 can be obtained also by heating 8 g. cyclohexylester of a-dimethylarninolauric acid with 3.2 g. benzyl chloride in 10 ml. acetone or dimethylformamide at 40 C. for 4 days.

(9) 8 g. benzylester of a-dimethylaminolauric acid is dissolved in 10 ml. acetone, to which solution 3.1 g. benzyl chloride is added with stirring, and the mixture heated for 2 days at 45 C. to be then allowed to stand for 4 days in a closed vessel without heating. The crystallized product is filtered by suction, washed with ether, and dried. There is obtained 6 g. et-carbobenzyloxyundecyl 1-benzyldimethylammonium chloride with M.P. C.

(10) 20 g. cthylester of a-dimethylarninopalmitic acid is added to a solution of 11 g. 3.4-dimeth0xybenzyl chloride in 40 ml. acetone, and after thorough mixing is allowed to stand for 3 days at normal temperature. Thereupon the acetone is distilled oil from the reaction mixture under reduced pressure without heating, whereby a yellowish-brown amorphous substance is obtained, which crystallizes after some time. The thus obtained crude quaternary salt is readily soluble in water, giving a clear solution, which forms a heavy sediment by shaking; the salt is soluble in alcohols, acetone and ether, while insoluble in petroleum ether; therefore it is purified by precipitation with petroleum ether from the ethereal solution, thus yielding an amorphous substance, which after some time crystallizes to form a light-yellow substance of fat-like consistence with a low M.P., the ot-carbethoxypentadecyl-/3.4-dimethoxybenzyl/ dimethylammonium chloride.

(11) 20 g. ethylester of a-dimethylaminolauric acid is dissolved in 20 ml. acetone, and under stirring 17.5 g. 3.4- dichlorobenzyl bromide is added. The reaction mixture is left in closed vessel for several days at normal temperature. The portion of the reaction product crystallized from the reaction mixture is filtered off and washed with ether, the latter then being united with the mother liquor, the organic solvents are evaporated, and the residue is left for several hours to crystallize. The crystallized quaternary salt is filtered off and washed several times with ether. In this way there is obtained 20.3 g. of a quaternary salt with M.P. 104 C.

(12) Using the same procedure as in Example 11 there is prepared a quaternary salt from 3.4-dichlorobenzyl bromide and n-propylester of a-dimethylaminolauric acid.

(13) Using the same procedure as in Example 11 a quaternary salt is prepared of 3.4-dichlorobenzyl bromide and isopropylester of a-dimethylaminolauric acid (having M.P. 98 C.).

We claim:

1. u-carbethoxypentadecyl benzyldimethylammonium chloride, with M.P. 106 C.

2. a-carbobutoxypentadecyl-benzyldimethylammonium chloride, With M.P. 74 C.

3. a-carbethoxypentadecyl-p-chlorobenzyl dimethylammonium chloride, with M.P. 126 C.

4. u-carbethoxypentadecyl-p-methoxybenzyl dimethylammonium chloride, with M.P. 112 C.

5. a-carbobutoxyundecyl benzyldimethylammonium chloride, with M.P. 92 C.

6. on carbocyclohexyloxyundecyl benzyldimethylammonium chloride, with M.P. 133 C.

7. a-carbobenzyloxyundecyl-benzyldimethylammonium chloride, with M.P. 105 C.

8. a-carbethoxylpentadecyl (3.4-dimethoxybenzyl)-dimethylammonium chloride.

3. u-carbethoxyundecyl-(3.4-dichtorobenzyl)-dimethylammonium bromide, with M.P. 104 C.

5 6 10. a-carbopropoxyundccyl (3.4-dich1or0benzyU-di- FOREIGN PATENTS methylamlnonium bromide. 0' C h I 11. a-carboisopropoxyundecyl-(3.4-dich10robenzyD-di' Zec Os ova methylammonium bromide, with M.P. 98 C. THER REFERENCES 5 CA. 60, 19486, Abstract of Czech. Patent No. 102,443.

References Cited UNITED STATES PATENTS NICHOLAS S. RIZZO, Primary Examiner.

2,459,062 2/1944 Cook et a1. 260-404 X F. A. MIKA,AssistantExaminer. 

